CHAPTER 2

Central nervous system

 Introduction
✢ CNS consists of the brain and spinal cord .
Brain
✢ Spinal Cord
✢ Central cavity surrounded by a grey matter (cell bodies) core .
Spinal
✢ External to which is white matter composed of myelinated fibre
cord
tracts.
✢ Brain
✢ Similar to spinal cord but with additional areas of grey matter.

✢ Cerebellum has grey matter in nuclei.

✢ Cerebrum has nuclei and additional grey matter in the cortex.

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 Brain Development
✢ Early brain research focus on size.
✢ It is assumes that brain size and intellectual
capacity are related.
✢ However, recent studies have revealed that
there is no clear relationship between brain
size and intelligence.
✢ The brain has increased in size.
✢ Most has occurred in the cerebrum.
✢ An increase in the number of convolutions.

3
 Brain Development
✢ In the months after birth the brain grows rapidly, producing billions of neurons,
dendrites and axons, as well as synapses reaching its peak around the infant’s first
birthday.
✢ In the first 2 years the brain increases in size from 25% to 75% of its adult weight.
✢ Soon after, synapses gradually disappear a phenomenon known as synaptic
pruning .
✢ Pruning makes the brain more efficient by eliminating underused connections.

4
 Brain Development
✢ There is a fivefold increase in the number of dendrites in cortex from birth to age 2
years, as a result approximately 15,000 new connections may be established per
neuron .
✢ This is called “Transient exuberance”.
✢ Transient exuberance : rapid proliferation of new neural connections in
infancy.
✢ These connections are necessary because thinking and learning require many
connections between many parts of the brain.
✢ Experience is vital for brain formation.

5
 Brain Development
✢ If cells are unused they atrophy and are rededicated to other senses.
✢ Underused neurons, like synapses are inactivated by pruning process .
✢ When children suffer brain damage, cognitive processes are usually impaired.
✢ These processes often improve gradually showing the brain’s plasticity .
✢ The brain’s organization is somewhat flexible and if damaged the brain can make
new connections.

6
 Brain Development
✢ The elimination and period of massive cell death is part of normal development
and maturation.
✢ After maturity, the apoptotic mechanisms become dormant.
✢ Neurons no longer need neurotrophins for survivals, but neurotrophins increase
the branching on axons and dendrites throughout life.
✢ Early stages of brain development are critical for normal development later in
life.
✢ Chemical distortions in the brain during early development can cause significant
impairment and developmental problems.

7
 Brain Development
✢ Fetal alcohol syndrome is a condition that children are born with if the
mother drinks heavily during pregnancy.
✢ The dendrites of children born with fetal alcohol syndrome are short with few
branches.
✢ Exposure to alcohol in the fetus brain suppresses glutamate and enhances the
release of GABA.
✢ Many neurons consequently receive less excitation and exposure to
neurotrophins than usual and undergo apoptosis.

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9
 Brain Development
✢ Children of mothers who use cocaine during pregnancy show a decrease in
language skills, a slight decrease in IQ scores and impaired hearing
✢ Children of mothers who smoked during pregnancy are at increased risk for low
birth weight, sudden infant death syndrome, ADHD, long term intellectual
deficits and impairments of the immune system.
✢ Smoking decreases oxygen in the blood, which can lead to neuron death and fetal
brain damage.
✢ Age brings some cognitive declines, but these are not significant in healthy
individuals until they reach their 80s

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 Brain Plasticity
✢ or neuroplasticity, is the lifelong ability to re-wiring
of brain pathways based on new experiences.
✢ The ability of the brain to reorganize neural
pathways based on new experiences.
✢ Persistent functional changes in the brain represent
new knowledge.
✢ Survivors of brain damage show subtle to
significant behavioral recovery.

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12
 Brain Plasticity
✢ Some of the mechanisms of recovery include those similar to the mechanisms of
brain development such as the new branching of axons and dendrites.
✢ After damage or injury
✢ Release from inhibition allows neurons to reorganize.

✢ Undamaged neurons make new connections and take over functionality or

establish new functions,
✢ But requires stimulation (phantom limb sensations),

✢ Stimulation standard technique for stroke victim rehabilitation,

13
 Brain Plasticity
✢ Possible causes of brain damage include
✢ Tumors

✢ Infections

✢ Exposure to toxic substances

✢ Degenerative diseases

✢ Closed head injuries

14
 Brain Plasticity
✢ A closed head injury refers to trauma that occurs when a sharp blow to the head
drives the brain tissue against the inside wall of the skull
✢ One of the main causes of brain injury in young adults

✢ A stroke or cerebrovascular accident is temporary loss of blood flow to the brain

✢ A common cause of brain damage in the elderly.

✢ One of the most effective laboratory methods used to minimize damage caused
by strokes is to cool the brain.

15
 Brain Plasticity
✢ Cannabinoids have also been shown to potentially minimize cell loss after brain
stroke, closed head injury and other kinds of brain damage.
✢ Benefits are most likely due to cannabinoids antioxidant or anti-inflammatory
actions.
✢ Application of omega-3 fatty acids, a major component of cell membranes, may
help to block apoptosis and other neural damage.
✢ Destroyed cell bodies cannot be replaced, but damaged axons do grow back under
certain circumstances.
✢ Damaged axons only regenerate 1 to 2 millimeters in mature mammals.

16
 Brain Plasticity
✢ Paralysis caused by spinal cord damage is relatively permanent.
✢ Scar tissue makes a mechanical barrier to axon growth.
✢ Myelin in the central nervous system also releases proteins that inhibit axon
growth.
✢ Collateral sprouts are new branches formed by other non-damaged axons that
attach to vacant receptors.
✢ Cells that have lost their source of innervation release neurotrophins that induce
axons to form collateral sprouts.
✢ Over several months, the sprouts fill in most vacated synapses and can be useful,
neutral, or harmful.

17
Brain Plasticity

18
 The Brain
✢ one of most metabolically active organs in body.
✢ Although it comprises only 2% of total body weight, the brain
✢ gets 15% of blood.

✢ consumes 20% of our oxygen need at rest and more when mentally active.

✢ Cerebral blood flow and cerebral metabolic rate are directly related to brain
activity.
✢ More blood flows to the area of the brain with high metabolic activity.
✢ 1-2 min interruption of blood flow may impair brain cells
✢ >4 min without oxygen cause permanent damage.

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 Divisions of the brain
✢ The human brain is hugely interconnected but
three major divisions can be identified.
✢ Cerebrum

✢ Cerebellum

✢ Brain stem – midbrain, pons, medulla

20
 Cerebrum
✢ largest portion of brain (~60% of brain mass).
✢ Split into symmetrical pairs in the left and right
hemispheres.
✢ The two hemispheres look similar, but are slightly
different in structure and perform different
functions.
✢ Each hemisphere acts contralaterally.
✢ Two hemispheres joined by tracts = corpus
callosum.

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 Cerebrum
✢ Responsible for the perception and conscious understanding of all sensations and
the integration of different sensory modalities.
✢ Involved in higher cognitive and advanced intellectual functions.
✢ Responsible for features such as emotion, personality and intellec.t
✢ Also involved in planning and executing complex, voluntary motor activities.

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 Cerebrum
✢ The cerebrum is covered by a sheet of neural tissue known as the cerebral cortex,
which envelops other brain organs such as the thalamus, the hypothalamus and
pituitary gland and pineal gland.
✢ only 2 - 4 mm thick.
✢ heavily convoluted: gyri and sulci, allowing a large surface area.
✢ 90% of all the brain’s neurons are located in the cerebral cortex.
✢ Divided into four main regions or lobes, which cover both hemispheres.

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24
 Cerebrum
✢ Gyri – bulges or folds (twisted ridges between
sulci)
✢ Sulci – shallow fissures
✢ Fissures – Deep grooves, generally dividing
large regions/lobes of the brain
✢ Longitudinal Fissure

✢ Transverse Fissure

✢ Sylvian/Lateral Fissure

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 Convolutions
Mouse
Brain

Human
brain

26
 Cerebrum
✢ Typical 6 layered cortex
✢ Molecular – local inhibitory interneurons

✢ External Granular – association neurons

✢ External Pyramidal – commisural neurons

✢ Internal Granular – receives thalamocortical projections

✢ Internal Pyramidal - projecting neurons (basal ganglia, brain stem, spinal cord
✢ Polymorphic – corticothalamic neurons

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 Molecular

External
Granular

External
Pyramidal

Internal
Granular

Internal
Pyramidal

Polymorphic

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 Thalamus
✢ Is the “gateway” to the cerebral cortex.
✢ Plays a key role in mediating sensation, motor activities, cortical arousal, learning,
and memory
✢ Afferent impulses converge on the thalamus
✢ Contains approximately a dozen major nuclei.
✢ Nuclei act as relay stations for incoming sensory messages.
✢ amplify or tone down signals

✢ Synapse in at least one of its nuclei

✢ Relays signals from cerebellum to motor cortex
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30
 Hypothalamus
✢ Hypothalamus links the nervous system to the endocrine system via pituitary
gland.
✢ Functions
✢ Control of the autonomic nervous system.

✢ Control of emotional responses.

✢ Regulation of body temperature, hunger and thirst sensations.

✢ Control of behavior.

✢ Regulation of sleep-wake cycles.

✢ Control of the endocrine system.

✢ Formation of memory.
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 Lobes of the Brain
1. Frontal 3. Occipital
✢ personality ✢ processing of vision
✢ control of voluntary movement

2. Parietal 4. Temporal
✢ touch, stretch ✢ processing of sound and speech
✢ perception of somatic sensations ✢ awareness of equilibrium

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Lobes of the Brain

33
34
Special regions
✢ Broca’s area
✢ located in the frontal lobe .

✢ Helps in producing coherent speech.

✢ Wernicke’s area
✢ comprehension of language and the production of meaningful speech.

✢ Aphasia is an impairment of language, usually caused by left damage either to

Broca’s area (impaired speaking) or to Wernicke’s area (impaired understanding).

35
 Aphasia
Disturbance of language caused by brain damage affecting:
✢ Comprehension

✢ auditory

✢ reading

✢ Expression

✢ speaking

✢ writing

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 Types of Aphasia
Boston Classification: Fluency Dimension
Two broad categories:
1. Non-fluent aphasias – there are difficulties in articulating or self-initiated
speech but relatively good auditory verbal comprehension (e.g., Broca’s severe,
Broca’s mild)
2. Fluent aphasias – fluent speech but difficulties either in auditory verbal
comprehension or in the repetition of words, phrases, or sentences spoken by
others (e.g., Wernicke’s or sensory aphasia; Anomic)

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 Non-fluent aphasias: Broca’s
aphasia
✢ Comprehension
✢ Reading comprehension relatively spared
✢ Expression
✢ Slow & effortful production
✢ Limited word output
✢ Four words or less per utterance
✢ Frequent perseverations
✢ Agrammatic
✢ Writing usually parallels oral expression
✢ Repetition
✢ poor 38
 Non-fluent aphasias
✢ Associated with damage in the frontal lobe.
✢ Not due to damage to the motor strip.
✢ Broca’s area (BA44 and 45).

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 Fluent aphasias: Wernicke’s
Aphasia
✢ Problems in comprehending speech – input or reception of language
✢ Fluent meaningless speech
✢ Paraphasias – errors in producing specific words
✢ Semantic paraphasias – substituting words similar in meaning (“barn” - “house”)
✢ Phonemic paraphasias – substituting words similar in sound (“house” - “mouse”)
✢ Neologisms – non words (“galump”)
✢ Deficit in categorization of sounds (e.g., “l” vs. “r”)
✢ Poor repetition
✢ Impairment in writing
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 Fluent aphasias
✢ Associated with damage to the temporal lobe
near but not including the Heschel’s gyrus
(primary auditory cortex; the patients are not
deaf)

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 Cerebellum
✢ helps to coordinate voluntary muscles but does not send impulses directly to
muscles
✢ acts with cerebrum to coordinate different groups of muscles
✢ controls skeletal muscles to maintain balance.
✢ learning and storing motor skills.
✢ diseases of cerebellum produce Ataxia.
✢ Eg: tremor, speech problems, difficulty with equilibrium
✢ NOT paralysis

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Cerebellar
Ataxia

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 Brain stem
✢ Has three parts – midbrain, pons and medulla oblongata.
1. Pons
✢ Connects cerebellum to brain stem and relays sensory input to cerebellum and
thalamus.
2. Midbrain
✢ Process visual and auditory sensory.

✢ Coordinating muscle motor movements.

✢ Maintains consciousness.

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 Brain stem
3. Medulla oblongata
✢ Regulates vital functions (cardiac, respiratory and vasomotor).

✢ Along with the pons, forms the ventral wall of the fourth ventricle.

✢ Contains a choroid plexus on the ventral wall of the fourth ventricle.

✢ Snipers trained to aim for medulla. Damage to this area causes target to collapse
immediately.

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Brain stem

46
 Reticular Formation
✢ Clusters of neurons in the brainstem that
plays an important role in controlling
arousal.
✢ Damage to reticular formation can cause
fatigue, changes in sexual arousal and
disrupted sleep patterns.
✢ Severe damage to the reticular formation
can lead to coma or death.

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48
 Reticular Formation
✢ Reticular activating system (RAS)
✢ Controls all cyclic functions i.e. respiration, circadian rhythm .

✢ Maintains consciousness and alertness.

✢ Functions in sleep and arousal from sleep.

✢ Filters out repetitive and week stimuli.

✢ Modulates sensation of pain.

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 Ascending Reticular
Activating System - ARAS
✢ Receives fibres from the sensory
pathways via long ascending spinal
tracts.
✢ Alertness, maintenance of attention and
wakefulness.
✢ Emotional reactions, important in
learning processes.
✢ Tumour or lesion – sleeping sickness or
coma
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 Descending Reticular
Activating System - ARAS
✢ Functionally divided into two subdivision namely
✢ Descending inhibitory reticular projection

✢ Descending facilitatory reticular projection

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 Spinal cord
✢ Connecting mechanism between the body (skin,
joints, muscles) & the brain.
✢ about 45 cm in length
✢ Enclosed in vertebral column.
✢ Communication with body
✢ 31 pairs of spinal nerves

✢ Dorsal root
✢ Ventral root
✢ Fluid-filled cavity
✢ Cerebrospinal fluid (CSF)
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Spinal cord

53
 Spinal cord

✢ Tracts carry information in only one direction along a specified path of interneuron
connections.
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Spinal cord:
Integrating
Center

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 Gray and White matter
✢ CNS contains both gray and white matter.
✢ Gray matter
✢ home to unmyelinated axons, dendrites, cell bodies, axon terminals and
synapse.
✢ outer layer of brain

✢ inner layer of spinal cord

✢ White matter
✢ consists of myelinated axons.

✢ inner layers of brain

✢ outer layer of spinal cord

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Gray and White matter

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 Gray and White matter
✢ Volume of gray matter in a particular region of the brain appears to correlate
positively with various abilities, skills and creativity.
✢ The density of cells is determined by both genes and environmental factors, such
as experience.
✢ Grey matter density in the brain increases during adolescence.
✢ Although female brains are smaller than males, they have larger gray
matter volume (Lotze et al., 2019).

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Lumbar puncture

Epidural
puncture 59
 The Meninges
✢ The membranous coverings of the brain and spinal cord.
✢ There are three layers of meninges, known as
✢ Dura mater (outer)
✢ Arachnoid mater

✢ Pia mater (inner)

✢ Cover and protect CNS

✢ Protect blood vessels and enclose venous sinuses
✢ Contains cerebrospinal fluid .

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61
 Dura Mater
✢ Latin for „Tough Mother’
✢ Two fused layers (periosteal and
meningeal) which splits to form venous
sinuses
✢ Surrounds brain, close to the skull (no
epidural space)
✢ Thick and leatherlike, contains pain
receptors (none in arachnoid, pia or brain)
✢ Composed of dense connective tissue

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 Arachnoid
✢ A soft, translucent membrane that loosely envelops the brain.
✢ Middle part of the meninges beneath the dura mater.
✢ made up of loose connective tissue.
✢ Provides cushioning effect for the CNS.
✢ Impermeable to fluids.
✢ It continues downwards over the spinal cord.
✢ The arachnoid is separated from the dura by
a narrow subdural space.

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 Pia Mater
✢ Latin for „Soft Mother’
✢ The innermost, thin, delicate & highly vascular membrane that is closely adherent
to the gyri and fitted into the sulci
✢ Adheres to brain via astrocytes.
✢ Impermeable to fluids.
✢ Between the pia mater and arachnoid
membrane lies the subarachnoid space.

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 Pia Mater
✢ Subarachnoid space
✢ Filled with CSF.

✢ Contains the blood vessels that

supply the brain.
✢ Arachnoid villi
✢ Allow CSF to pass into the dural
blood sinuses.

65
Intracranial Haemorrhage
✢ Three types of hemorrhage involving the meninges.
✢ Epidural hematoma is a traumatic accumulation of blood between the inner
table of the skull and the stripped-off dural membrane.
✢ Subdural haemorrhages may cause an increase in intracranial pressure (ICP),
which can cause compression of and damage to delicate brain tissue.
✢ The blood may be aspirated surgically to remove the mass and reduce the
pressure it puts on the brain .
✢ A subarachnoid hemorrhage is acute bleeding under the arachnoid which may
occur spontaneously or as a result of trauma.

66
Computed Tomography images
68
 Meningitis
✢ Inflammation of the meninges.
✢ Disease of infancy and childhood.
✢ Between 3 months and 2 years of age.
✢ Bacterial and virus invasion of the CNS by way of the nose and throat.
✢ Signs include high fever, stiff neck, drowsiness and intense headache and may
progress to coma.
✢ Diagnose by examining the CSF.
✢ Lumbar puncture (spinal tap).

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71
 Brain ventricles
✢ A communicating network of cavities filled with cerebrospinal fluid (CSF).
✢ There are four ventricules
✢ 2 lateral ventricles are in the brain hemispheres

✢ the third ventricle is single vertical space under corpus callosum

✢ the fourth ventricle between the pons, medulla and the cerebellum.

✢ the cerebral aqueduct connects the third and fourth ventricles

✢ Central canal runs down through spinal cord.

✢ Lined with ependymal cells and containing choroid plexus of capillaries that
produce CSF.

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Brain ventricles

73
 The Cerebrospinal Fluid
✢ Fluid surrounding the brain and the spinal cord
✢ In subarachnoid space.

✢ Adult total volume 140-170 ml.

✢ Functions
✢ Supports and cushions the brain

✢ Protects the brain from blows and trauma

✢ Helps nourish the brain

✢ Transport chemical signals (hormones, etc.)

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 The Cerebrospinal Fluid
✢ Secretes by the choroid plexuses (= ependymal cells plus capillaries in brain
ventricles).
✢ Choroid Plexuses
✢ Clusters of capillaries that form tissue fluid filters, which hang from the roof
of each ventricle
✢ Have ion pumps that allow them to alter ion concentrations of the CSF

✢ Help cleanse CSF by removing wastes

✢ Choroid plexus secretes ~500ml/day.

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The Cerebrospinal Fluid

76
 The Cerebrospinal Fluid
✢ CSF is produced at the same rate it is reabsorbed to maintain constant pressure
✢ production volume = absorption volume
✢ Volume of CSF in brain and cord turned over every 8 hrs (replaced completely up
to three times per day).
✢ CSF moves freely through the ventricles, subarachnoid space & central canal (in
spinal cord).
✢ Absorption occurs at the arachnoid villi into sagittal dural sinus.
✢ CSF is similar to plasma: glucose, proteins, white blood cells & ions.

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 The Cerebrospinal Fluid
✢ CSF forms in the choroid plexi of the lateral ventricles and flows into the third
ventricle through the interventricular foramina.
✢ The third ventricle adds to the CSF volume.
✢ The CSF then flows into the fourth ventricle via the cerebral aqueduct (passes
through the midbrain) – contributes more volume.
✢ Then enters the subarachnoid space via openings in the fourth ventricle called
apertures.
✢ Also enters the central canal of the subarachnoid space.
✢ Circulation is driven by ciliary action and pressures provided by the blood and
gravity – 10 mm Hg.
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79
 Hydrocephalus
✢ Failure to reabsorb CSF,
fluid expands cranium and
crushes brain.
✢ Can occur at any age, but is
most common in infants
and adults age 60 and older.
✢ Implantation of a shunt –
lateral ventricle into the
superior vena cava or
abdomen.

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Hydrocephalus

81
 The Blood Brain Barrier
✢ The brain is a privileged site sheltered from the systemic circulation by the blood
brain barrier (BBB).
✢ Highly specialized brain endothelial structure of the fully differentiated
neurovascular system.

82
The Blood Brain Barrier

83
 The Blood Brain Barrier
✢ Normal neuronal-vascular relationship is critical for normal brain functioning.
✢ Estimated that every neuron has a capillary.
✢ Human brain: total length = 650 km.
✢ Capillary surface area available for molecular transport = 20 m2
✢ Length of brain capillaries is reduced in neurodegenerative disorders (e.g. AD).
✢ Vascular reductions diminish transport of energy substrates and nutrients across
the BBB and reduce the clearance of neurotoxins from the brain.

84
The Blood Brain Barrier

The brain The network of capillaries Brain capillaries from

the human cerebellar
cortex

85
The Blood Brain Barrier

Cells in the brain lie in extracellular fluid

86
 The Blood Brain Barrier
✢ Primary role of the BBB
✢ It separates components of the circulating blood from neurons and so
maintains the chemical composition of the neuronal microenvironment.
✢ A stable microenvironment is required for
✢ Proper functioning of neuronal circuits.

✢ Synaptic transmission.

✢ Synaptic remodelling.

✢ Angiogenesis - the formation of new blood vessels.

✢ Neurogenesis - the formation of new neurons from neural stem and

progenitor cells.
87
 The Blood Brain Barrier
✢ Cerebral capillary endothelium and
periendothelial structures.
✢ A highly selective barrier.
✢ Formed by endothelial cells lining the
cerebral microvessels.
✢ Continuous tight junctions present
between brain endothelial cells.
✢ Astrocytes cover capillary surface.
✢ Physical & chemical barrier between
blood and neuronal tissue.
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The blood vessel endothelial cells of the BBB
are cemented together by protein structures
called tight junctions (1) .
BBB endothelial cells display transporters
(2) to prevent diffusion of most molecules
between cells.
receptors (3), channels (4) and efflux
pumps (5) facilitate selective transport of
vital nutrients into the CNS.
Pericytes and astrocyte pseudopods serve as
an additional physical barrier between the
blood vessel and brain tissue, and support the
expression of endothelial cell genes required
to maintain the BBB.

89
 The Blood Brain Barrier
✢ A “filter” mechanism
✢ Prevents many substances crossing
between blood & brain
✢ It protects the brain from pathogens and
endows a relative immune privilege.

90
 The Blood Brain Barrier
✢ Very small molecules can get between cells.
✢ Fat-soluble substances are more likely to get through cell membranes.
✢ Chemical substances can also move across barrier if they have carriers.
✢ Some substances cross with help of receptors.
✢ Some areas of blood-brain barrier are weaker than others
✢ Absent in some areas (vomiting centre and portions of the hypothalamus),
allowing these areas to monitor the chemical composition of the blood.
✢ Also absent in portions of pineal gland and capillaries that supply choroid
plexuses.

91
 The Blood Brain Barrier
✢ Barrier” suggests relatively fixed structure
✢ BBB phenotype subject to change/modulation
✢ Opening of BBB’s tight junctions can occur in inflammation, contributing to
brain edema.
✢ Upregulation of GLUT1 transporter experimentally observed in starvation
and hypoxia.
✢ Some of the inflammatory mediators that increase capillary permeability in
the periphery (histamine, bradykinin) also act on brain endothelium.

92
93
94
 Blood–brain barrier
breakdown
• promotes cerebral
complications.
• an early biomarker of human
cognitive dysfunction
(Nation et al., 2019). 95
 Drug penetration across
blood–brain barrier
✢ Diseases of the CNS constitute 38% of the global economic health burden.
✢ Intact BBB is a major obstacle.
✢ Approximately 98% of small molecule drugs and all large nanotherapeutics
excluded from the brain.

96
 Therapy
✢ While most medications treating mental illnesses such as schizophrenia and
depression are small-molecule, lipid soluble compounds capable of crossing the
BBB, other CNS treatment currently cannot do this.
✢ Genes responsible for many of these disorders including Alzheimer’s disease,
Huntington’s disease, and Parkinson’s disease are known, but there is currently no
way large enzymes can be delivered to the brain using gene therapy.
✢ In the case of Parkinson’s disease, L-Dopa, used to alleviate symptoms, can enter
the brain, but provides only temporary relief

97
Approaches for Brain Drug
Delivery
✢ Non-invasive techniques
✢ chemical structure transformation of drugs to improve their unsatisfactory
physicochemical properties
✢ Invasive techniques
✢ Trans-cranial drug delivery involves the medication being injected or inserted
into the brain itself .
✢ Intracerebral implants.

98
Approaches for Brain Drug
Delivery
✢ Alternative routes for CNS drug delivery
✢ Trans-nasal drug delivery to the brain
via the nasal cavity has also been
considered, but it has been found that this
only works for certain small molecules and
in limited quantities.
✢ Iontophoretic delivery - a method to
deliver ionized molecules across the BBB by
using an externally applied electric current.
99
Approaches for Brain Drug
Delivery
✢ BBB disruption
✢ solutes such as mannitol are used to
shrink the brain’s endothelial cells,
allowing various molecules to pass into
the cerebral tissue. Trials to date,
however, have revealed serious side
effects associated with this treatment.
BBB disruption by physical forces

100
101
102
 Brain wave
✢ Normal brain function involves continuous electrical activity.
✢ Patterns of neuronal electrical activity recorded are called brain waves.
✢ Each person’s brain waves are unique.
✢ Abnormal electrical activity can signal epilepsy or mental illness.
✢ Wave frequency is expressed in Hertz (Hz).
✢ The amplitude of the EEG pattern is strength of the pattern in terms of
microvolts of electrical energy.

103
 Brain wave
✢ Brain waves are rhythmic fluctuation of electric potential between parts of the
brain as seen on an electroencephalogram (EEG).
✢ To measure brain waves electrodes are placed onto the scalp using the EEG.

✢ Brain waves have been categorized into four basic groups :

✢ Beta (14-25 Hz)

✢ Alpha (8-13 Hz)

✢ Theta (4-7 Hz)

✢ Delta (1-3 Hz)

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105
 Brain wave
✢ Alpha waves
✢ 8-13 Hz.

✢ Associated with relaxed wakefulness (awake or resting with eyes closed.

✢ Disappear during sleep.

✢ Increased seratonin production.

106
 Brain wave
✢ Beta waves
✢ 14-25 Hz.

✢ Seen in individuals who are awake, alert, with eyes open, and who may be
performing mental tasks.
✢ Associated with alertness, concentration and learning.

✢ Higher levels associated with anxiety, fear and stress.

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 Brain wave
✢ Theta waves
✢ 4-7 Hz.

✢ Seen in adults sleeping and in children .

✢ Associated with increased learning and memory, creativity, deep meditation.

✢ Allow access to the unconscious.

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 Brain wave
✢ Delta waves
✢ 1-3 Hz or less

✢ Deep sleep in adults

✢ Normal in awake infants

✢ During anesthesia

✢ Their abnormal appearance in awake adults can be indicative of a brain tumour.

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 Brain wave
✢ Change with age, sensory stimuli, brain disease, and the chemical state of the body
✢ EEGs can be used to diagnose and localize brain lesions, tumors, infarcts,
infections, abscesses, and epileptic lesions.
✢ A flat EEG (no electrical activity) is clinical evidence of death.
✢ Consciousness is a state of arousal in which the brain is aware of self and
environment.
✢ Reticular formation is actively interacting through ascending tracts.

✢ Anesthetics block signals from reaching the reticular formation.

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 Brain wave
✢ Awake state
✢ Uncoordinate firing of cortical neurons due to ascending signals in reticular
formation results in low-amplitude high-frequency waves.
✢ As awareness declines signals the frequency of waves declines and amplitute
increases.
✢ Sleep is a temporary state of unconsciousness.
✢ Major rest period for the body, no external interaction, easily reversible, brain
is as active as when awake, sleep inducing factors also boost immunity.
✢ Coma is state of unconsciousness with no possible arousal.

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 Sleep
What is sleep?
✢ state in which the brain actively produces moderate decrease in brain activity
and decreased response to stimuli
Functions of sleep
✢ Energy conservation

✢ decrease in body T of about 1-2 °C in mammals

✢ decrease in muscle activity.

✢ Restoration of the brain and body
✢ Memory consolidation

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 Stages of Sleep
✢ Usually sleepers pass through four stages (occurring in first 30 to 45 minutes of
sleep)
✢ Stage 1 is drifting sensation (would claim was not sleeping).
✢ Stage 2 still easily aroused. Heart rate slows, brain does less complicated tasks.
✢ Stage 3 vital signs change - BP, pulse & breathing rates drop ( reached in 20
minutes).
✢ Stage 4 is deep sleep - difficult to arouse.
✢ Parasomnias (sleepwalking, sleep talking or somniloquy and night terrors) occur
during the deepest stage of sleep.

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 Stages of Sleep
✢ Rapid eye movements (REM) sleep occurs about 5 times a night
✢ vital signs increase, EEG resembles awake person, dreams and penile erections
occur
✢ May help sort and strengthen information from memory.
✢ REM sleep periods become longer and more frequent in the second half of the
night
✢ Brain waves change as we pass through 4 stages of sleep: alpha, to sleep spindles, to
theta and finally to delta waves during deep sleep.

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 Importance of Sleep
✢ Slow-wave sleep (NREM stages 3 and 4) is presumed to be the restorative stage
✢ Brain glycogen levels increase

✢ Memories strengthened by reinforcing or eliminating synaptic connections.

✢ People deprived of REM sleep become moody and depressed.

✢ REM sleep may be a reverse learning process where superfluous information is
purged from the brain.
✢ Daily sleep requirements decline with age.
✢ Stage 4 sleep declines steadily and may disappear after age 60.

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NEUROTRANSMITTERS & SLEEP

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 Sleep centers
✢ Raphe nuclei in lower pons and medulla
✢ Targets (efferents): Reticular formation, thalamus, neocortex, hypothalamus,
limbic system, dorsal roots of spinal cord
✢ Neurotransmitter: Serotonin (5HT)

✢ Medullary synchronization area

✢ Diencephalic sleep areas
✢ Basal forebrain sleep area

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 Sleep disorders
✢ Narcolepsy
✢ frequent and unexpected periods of sleepiness.

✢ Symptoms: gradual or sudden attack of sleepiness, occasional cataplexy (muscle

weakness), sleep paralysis (inability to move when asleep), hypnagogic
hallucinations (dreamlike experiences).
✢ Cause: seems to run in families (no gene identified), lack of hypothalamic cells

✢ Treatment: stimulant drugs (e.g. Ritalin)

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 Sleep disorders
✢ Insomnia
✢ inadequate sleep.

✢ Normal cause: noise, stress, pain, diet, medication.

✢ Other causes: epilepsy, Parkinson’s disease, depression, anxiety or other

conditions.
✢ Dependence on sleeping pills or alcohol and shifts in the circadian rhythms can
also result in insomnia

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 Sleep disorders
✢ Sleep apnea
✢ inability to breathe while sleeping for a prolonged period of time

✢ Consequences: sleepiness during day, impaired attention, depression, heart

problems
✢ Causes: genetic, hormones, old age, deterioration of brain mechanisms that
control breathing and obesity
✢ Cognitive impairment may result

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Neuroanatomical Techniques
These tell us about the anatomical structure of the brain
A. Histological Procedures
✢ Gross examination of the brain does not allow us to study details of cell structure
and connectivity, to do so we need to selectively stain thin slices of the brain
✢ After death the soft brain tissue is destroyed by autolytic enzymes, so the brain
must be preserved with a fixative, such as formalin
✢ The brain is then embedded within a paraffin block that can be sliced thinly using
a microtome and mounted on slides
✢ Histological stains have been developed so that cell bodies, nerve fibres and
membranes can be selectively viewed
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Cell-body stains Myelin stains

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Neuroanatomical Techniques
B Tracing Connections
Anterograde (forward) tracing
✢ Certain proteins taken up by cell bodies are transported through axons until
they reach the terminal buttons .
✢ Lectins such as phaseolus vulgaris leukoagglutinin (PHA-L) are often used

Retrograde (backward) tracing

✢ Dyes such as flurogold are injected into the terminal buttons and are then
carried back through the axons to the cell bodies where they can be seen

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PHA-L anterograde tracing

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Neuroanatomical Techniques
C Histochemical Techniques
✢ These tell us the location of specific neurons that produce and secrete
particular neurotransmitters.
✢ Antibodies for a specific neurotransmitterare injected into a region and the
slides are viewed under ultraviolet light.
✢ Alternatively radioactive 2-deoxyglucose (2-DG) is taken up by active
neurons.

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 Neuroimaging Techniques
Recording Brain Activity
✢ The methods previously described have all required the brain to be removed

✢ The following techniques enable neural structure and function to be viewed in

the living brain.
Non-invasive, measure blood flow (+ spatial resolution)
✢ PET (positron emission tomography)

✢ fMRI (functional magnetic resonance imaging)

✢ Optical imaging

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PET Scan

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 Neuroimaging Techniques
✢ Non-invasive, meassure electrical activity (+ temporal resolution)
✢ EEG

✢ ERP (event related potentials)

✢ MEG (magneto-encephalography)

✢ Invasive, measure electrical activity (+ temporal and spatial resolution)

✢ Single unit recording

✢ Cortical recording

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 Neuroimaging Techniques
Advantages
✢ Non-invasive (CAT, MRI)

✢ Provide very detailed knowledge about structure (CAT, MRI) and function (PET,
fMRI)
Disadvantages
✢ Mildly invasive (PET)

✢ Only provide horizontal pictures (CAT)

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